1. Technical Field
The present invention relates, in general, to the preparation of platinum-containing compositions to be used for the localization and/or treatment of tumor cells and, in particular, to the preparation of water-soluble platinum-containing macromolecules covalently attached to targeting agents such as monoclonal antibodies, antibody fragments or bioactive peptides.
2. Background Information
The platinum-containing antitumor compound cisplatin is now widely used as a drug for various neoplastic disorders with high efficacy in certain instances. While its exact mode of action is still disputed, it is generally agreed that platinum causes intrastrand crosslinks in DNA which block transcription and effectively halt tumor growth. A major problem with cisplatin as a drug, however, aside from the nausea and vomiting which cause extreme discomfort for the patient, is its severe dose limiting nephrotoxicity. The search for cisplatin analogs with similar antitumor properties, less toxic side effects and a broader range of activity, has produced carboplatin, a diamine malonato platinum complex, which is now used clinically. The decreased nephrotoxicity is believed to be due to the greater in vivo stability of the malonate ligand compared to the chlorides of cisplatin.
To improve the chemotherapeutic activity of platinum complexes, efforts have been made to utilize targeting agents, like monoclonal antibodies, to selectively deliver platinum to tumor cells, thereby avoiding the toxic side effects associated with intravenous or intraperitoneal administration, while achieving a therapeutic dose. See: Heffernan, J. G. et al EPO No. 167,310 and EPO No. 169,645 and Hurwitz, E. et al EPO No. 99,133. The use of biodegradable implants containing cisplatin has been described. See: Drobnik, J. and Stepankova, H. GB No. 2,160,422. In addition, the use of macromolecules to carry a drug to a tumor site has also been suggested. Drug-carrier conjugates prepared to date include mitomycin C-dextran; 5-fluorouridine-dextran and cytosine arabinoside-dextran; methotrexate-poly-L-lysine; daunorubicin-polyglutamate and daunorubicin-dextran; and adriamycin-polyvinyl alcohol. See: Sezaki, H. et al (1980) J. Pharm. Pharmacol. 32, 30-34 and Chem. Pharm. Bull (1985) 33, 2941-2947; Hurwitz, E. et al (1985) J. Med. Chem. 28, 137-140; Rosowsky, A. et al (1985), Mol. Pharm. 27, 141-7; Hurwitz, E. et al (1980) J. Appl. Biochem. 2, 25-35; and Wingard, L. B., Jr. et al (1985) Cancer Res., 45, 3529-3536.
In general, these macromolecular drug conjugates have proven to be less toxic than the monomeric drug while being equally or more effective in killing cancer cells. Of the platinum(II)-containing macromolecules which have been prepared to date and tested for biological activity all but one, Meshnick, S. R. et al (1984) Antimicrobal Agents Chemother. 25, 286-288, are conjugates of platinum(II) dichlorides. See: Alcock, H. R. et al (1976) J. Chem. Soc. Chem. Comm., 717; Carraher, C. E. et al (1984) Polym. Mater. Sci. Eng. 49, 210214 and 51, 307-311; Hurwitz, E. et al (1982) JNCI 69, 47-51 and EPO No. 99,133; De Clerq, E. et al (1983) Biochem. Biophys. Acta. 741, 358-363; and Takahaski, K. et al (1985) Jpn. J. Cancer Res. (Gann) 76, 68-74. As such, they readily form active platinum-(aquo).sub.n species which accounts for the observed cytotoxicity, but bind ligand quickly and sometimes irreversibly upon formation.
In addition to binding serum proteins, platinum-(aquo).sub.n species can oligomerize monoclonal antibody. Not only is drug stability highly questionable in these conjugates, but the incompatibility of drug with targeting agent makes these platinum(II)-containing carriers poorly suited for targeted chemotherapy. The only conjugate which does not contain Pt(II) dichlorides is a highly crosslinked platinum(II) dicarboxylate, and as such is not only poorly characterizable but probably highly immunogenic. To date very little effort has thus been made to design and control the chemistry of attaching antitumor platinum compounds to carrier macromolecules.